The causes of Alzheimer's (AD) and Parkinson's (PD) remain enigmatic and treatment options, although improving, are limited. Numerous studies now point to impaired mitochondrial function as a key problem associated with the pathogenesis of AD and PD as well as the normal aging process. CNS neurons have a complex morphology and are critically dependent on mitochondria to produce a large, uninterrupted supply of ATP and regulate Ca/2+ in their cell bodies, processes and synaptic terminals. Synaptic terminal degeneration is a hallmark of both AD and PD. Therefore, the distribution and localization of defective mitochondria, which are sites of excess free radical production, to synaptic terminals could have significant functional consequences relevant to these neurodegenerative diseases. How neurons localize, regulate and maintain a steady-state distribution of mitochondria to sites of intense energy utilization (i.e. synaptic terminals) is not well understood. Even less i known about how mitochondrial movement is altered in neurons containing functionally- compromised mitochondria. In this proposal, we will study a model system using cytoplasmic hybrid (cybrid) cells created from the fusion of age- matched patient (AD and PD) and control platelet mitochondria with SH-SY5Y human neuroblastoma cells (p cells) that are deficient in mitochondrial DNA (mtDNA) as well as the primary neurons. using this model we will examine hypotheses about the movement of normal, and defective (functionally compromised or impaired) mitochondria in differentiated AD, PD and control cybrids and in primary neurons in vitro to determine if mitochondrial movement is kinetically-altered when function is impaired. These studies are significant because altered mitochondrial movement in susceptible neurons could lead to compromised function in metabolically- demanding structures such as synaptic terminals and ultimately led to the terminal degeneration that is characteristic of both AD and PD.